Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
J Med Chem. 2015 Jan 8;58(1):517-21. doi: 10.1021/jm500362j. Epub 2014 May 2.
Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.
磷酸肌醇 3-激酶 γ（PI3Kγ）是一个有吸引力的靶点，可能用于治疗一系列疾病状态。在此，我们描述了报道的苯基噻唑泛 PI3K 抑制剂向一组强效和选择性苯并噻唑抑制剂的进化。通过 X 射线晶体学，我们发现化合物 22 占据了一个以前未报道的紧邻 PI3Kγ 的 ATP 结合位点的疏水性结合口袋，并且通过利用该区域中 PI3K 同工型之间的天然序列差异来实现其选择性。
